The transforming growth factor beta (TGF-beta) signaling pathway, which is mediated through the TGF-beta receptor complex consisting of the type I and type II TGF-( receptors (TGFBR1 and TGFBR2), is essential for normal growth and development as well as for stress responses in many organs, including the liver. Stimulation of this pathway can regulate cell growth and death through 1) affecting cell cycle progression, 2) mediating differentiation, and 3) inducing apoptosis in epithelial cells. TGF-beta can also mediate extracellular matrix remodeling, induce neoangiogenesis, and probably regulate genomic stability. Because of the complex nature and multiple functions of TGF-beta, we have developed a novel liver-specific Tgfbr2 knock-out mouse, the Tgfbr2 hepk mouse, in order to study the physiologically relevant effects and mechanisms of TGF-beta signaling in vivo. TGF-beta signaling has been shown to play a role in 1) the regulation of liver cell proliferation, 2) the regulation of apoptosis, and 3) the formation of hepatocellular carcinomas (HCC); however, the in vivo effects of TGF-beta on hepatocyte proliferation, apoptosis, and transformation are largely unknown. The liver's unique proliferative capabilities make the Tgfbr2 hepk mouse an unparalleled model system to study TGF-beta's effects on cell proliferation and apoptosis in vivo and to determine TGFBR2's role in liver regeneration, liver mass regulation, and HCC formation. The specific aims of this proposal are to: 1) To determine the role of Tgfbr2 in liver mass regulation and the in vivo effects of TGF-( signaling on hepatocyte proliferation and apoptosis in the context of mass regulation; 2) To determine the in vivo role of Tgfbr2 on the regenerative response of the liver after partial hepatectomy; and 3) To determine the in vivo effect of loss of TGF-beta signaling in hepatocytes on hepatic carcinogenesis. This model will provide a novel and important in vivo system for investigating the complex role of TGF-beta signaling in hepatocyte proliferation and apoptosis and should yield novel insights into the relevant effects of TGF-beta signaling on liver regeneration, liver mass regulation, and liver cancer formation.